Bronchopulmonary dysplasia (BPD) is a chronic lung disease that occurs in preterm infants following mechanical ventilation and high levels of supplemental oxygen. While survival of premature newborns has increased due to recent improvements in perinatal care, BPD remains a serious and common complication of prematurity, affecting approximately 15,000 infants annually in USA. Infants with BPD are at higher risk of respiratory morbidity and mortality in early childhood. BPD has long-term respiratory and neurodevelopmental complications that reach beyond childhood and increase health care costs. Given the lack of major improvements in prevention and treatment of BPD, there is a major need for innovative molecular approaches to complement existing BPD therapies. Promising therapeutic approaches for BPD treatment include increasing postnatal angiogenesis and protection of alveolar endothelial cells from apoptosis after the injury caused by mechanical ventilation and high levels of oxygen. Based on our preliminary results, we believe that Forkhead Box F1 (Foxf1) transcription factor (also known as HFH-8 and Freac-1) plays a key role in both these processes and therefore, targeting the Foxf1 can be beneficial for both chemoprevention and treatment of children with BPD. Published studies from my laboratory have demonstrated that Foxf1 is expressed in pulmonary endothelial cells (EC) of embryonic and neonatal lungs. Mice heterozygous for the Foxf1 null allele exhibited lung hypoplasia, decreased number of alveolar capillaries, increased apoptosis of EC, and increased mortality in the early neonatal period. Genomic mutations in FoxF1 gene locus were recently found in 30% of human patients with Alveolar Capillary Dysplasia (ACD), a congenital lethal lung disease. Pulmonary Foxf1 mRNA and protein levels are reduced in newborn mice exposed to hyperoxia, a mouse model of BPD. Diminished Foxf1 levels are associated with loss of pulmonary vasculature in hyperoxia-treated newborn mice and human patients with BPD. Given the critical role of Foxf1 for pulmonary vascular development in mice and humans, it is important to determine the role of Foxf1 in the pathogenesis of BPD. We will use hyperoxia- mediated lung injury in newborn mice as a model of BPD to test the hypothesis that Foxf1 is required to maintain normal lung morphogenesis after hyperoxia injury by stimulating angiogenesis and increasing survival of endothelial cells. In Aim I, we will determine whether Foxf1 is required for formation of new pulmonary capillaries in a BPD model using two transgenic mouse lines with Foxf1 deficiency: Foxf1 mice and Tie2-Cre- fl/fl ER Foxf1 mice. In Aim II, we will determine whether Foxf1 directly regulates expression of anti-apoptotic genes and is required for survival of endothelial cells in a BPD model. Since the long-term goal of our studies is to find novel therapeutic agents preventing BPD in human patients, in Aim III we will determine whether increasing Foxf1 levels in neonatal lungs will accelerate vessel formation, increase EC survival and prevent BPD. Foxf1 levels in hyperoxia-treated newborn mice will be increased by either pharmacological approach (TAT-Foxf1 fusion protein) or genetic approach (Doxycycline-inducible over-expression of Foxf1 in endothelial cells). Completion of these studies will determine whether increasing Foxf1 levels is a promising therapeutic approach to prevent endothelial apoptosis and induce angiogenesis in BPD patients.